Chlamydia trachomatis infection is a leading cause of infertility and ectopic pregnancy in women. Although antibiotic therapy eliminates infection, it does not ameliorate established pathology. The protective immunity that develops in response to infection is not long-lived, and animal models indicate that repeated infection elicits worse disease. An improved understanding of the immunopathogenesis of chlamydial disease is needed to develop a rational vaccine strategy to combat the epidemic of chlamydial infection. TLR2-deficient mice do not develop oviduct pathology after chlamydial infection, demonstrating that TLR2 signaling is a key mechanism involved in disease development. We have derived novel plasmid-deficient C. muridarum mutants that retain the ability to infect the murine genital tract, but fail to cause disease. These mutants fail to stimulate TLR2 signaling in cell culture and in vivo and can be used to examine the role of TLR2 in pathogenesis in an immunologically normal host. Based on our observations in the mouse genital tract model, each of the following mechanisms contribute to development of oviduct pathology: 1) TLR2-mediated hyper-activation of innate immune cells leading to an excessive response beyond that required for bacterial clearance, 2) TLR2-mediated hyper-activation of the CD4 T cell response leading to overzealous Th1 activation and induction of Th17 cells that promote tissue-damaging neutrophil responses, 3) alterations in TLR2-independent MyD88-dependent response(s) that lead to prolonged infection and ongoing inflammation which contributes to tissue pathology. We propose the following specific aims: 1. Determine TLR2-mediated effects on innate immune responses during chlamydial infection that promote oviduct pathology. Aim 2: Determine the adaptive T cell responses induced in the absence of TLR2 signaling which lead to resolution of chlamydial infection in the absence of tissue damage. We will investigate the role of Tregs in limiting pathology and of Th17 cells in induction of pathology. Aim 3: Determine MyD88-dependent innate responses required for efficient chlamydial killing and generation of Th1 adaptive immunity. We will also examine the role of non-TLR2 receptors upstream of MyD88 in chlamydial host defense.